Tuberculosis is a disease with global health implications. Control of the disease utilizes a large amount of resources, with the greatest morbidity and mortality costs in resource-poor areas of the world. Despite dedicated research efforts, several aspects of the role of the host immune system in Mycobacterium tuberculosis infection remain beyond our understanding. We maintain that a better understanding of immunity in the course of tuberculosis disease will lead to identification of individuals or populations at increased risk of progressing to tuberculosis disease or developing more severe illness, as well as new targets for tuberculosis treatment. To this end, we would like to focus our attention on host immunity in tuberculosis infection, particularly, the role of the innate mediator, macrophage migration inhibitory factor (MIF). MIF is known to participate in the pathogenesis of a variety of rheumatologic and infectious diseases. While it is thought to contribute to detrimental inflammation in rheumatoid arthritis, vasculitis, and animal models of shock, it is crucial to control of infection with intracellular pathogens (Salmonella, Toxoplasma, and Leishmania). For this application, we will investigate the role of MIF in tuberculosis pathogenesis with special attention to innate immunity, establish the phenotype in a murine model, and perform a preliminary investigation of functionally significant MIF polymorphisms in a population of patients with tuberculosis. Using mycobacterial infection of MIF-deficient macrophages we will address the role that MIF plays in recognition of the pathogen, production of inflammatory mediators (cytokines, nitric oxide, reactive oxygen species), and macrophage function (activation-induced apoptosis and phagocytosis). We next will pursue tuberculosis infection in wild type and MIF-deficient mice to ascertain the role of MIF in survival, mycobacterial control, and pathology. Additionally, human polymorphisms in the MIF gene have been identified, which create high-producers and low-producers of MIF in population. Low-producers of MIF have increased susceptibility to some infectious pathogens, whereas they are relatively protected from others. For the final stage of our investigation, we will utilize MIF genotyping techniques in a population of patients with pulmonary tuberculosis and matched controls, to determine whether low-producers of MIF are identified more frequently among tuberculosis infected patients. Based upon results we obtain in this first study of the effect of MIF in the pathogenesis of tuberculosis, we plan to pursue larger population investigations of MIF genotype and the risk of progressing from tuberculosis infection to disease, and begin to assess the therapeutic implications for MIF's role in innate immune responses to tuberculosis infection. PUBLIC HEALTH RELEVANCE: Tuberculosis is a disease with global health implications. This project aims to better understand the interactions between the bacterium that causes tuberculosis and the immune system of the infected host. The goal of this research is to help determine factors that affect susceptibility to tuberculosis, and identify ways to boost immunity as a strategy in combating the disease.